Purification of Blood in Dialysis Patients
End-stage renal failure (ESRF) is an increasingly prevalent and disproportionately costly condition. The majority of patients receiving renal replacement therapy (RRT) undergo haemodialysis (HD) which primarily removes small water soluble molecules. However, most protein bound and larger molecular weight uremic toxins remain in the body, impairing cardiovascular function and contributing to the morbidity and mortality of HD patients. ESRF maintains a high morbidity and mortality rate despite improved therapy options. A complex picture is emerging of the pathophysiology associated with CKD progression in which newly identified uremic toxins not removed by HD appear to play a central role. A clinically effective and cost efficient device could transform ESRF patient care. Uremic toxin retention in renal failure is a complex problem that cannot be adequately modelled by measuring simple markers like urea and creatinine Middle molecules and protein bound molecules are not very efficiently removed by current dialysis therapies and may be very important mediators of pathology associated with chronic kidney disease. The removal of currently “difficult to remove” uremic toxins may diminish complications, extending and greatly improving patient quality of life. No cost-effective and clinically efficient devices exist currently.
U.S. Pat. No. 4,169,051 Satoh is concerned with the use of activated carbon as an adsorbent for the purification of blood in dialysis patients. It discusses the use of crushed activated carbon of vegetable origin but mentions problems of carbon dust and platelet adhesion which are not overcome by coating. Furthermore the crushed activated carbon cannot adsorb materials of medium molecular weight e.g. so-called “kidney toxin”. Molecular weight in this context is explained in U.S. Pat. No. 5,194,157 Ghezzi, “medium molecules” being defined as those of molecular weight 300-1500 D. Granular activated carbon was said to have superior properties with regard to dust but is poorly adsorbent. The proposed solution is to use beads of activated carbon derived from pitch and coated with a semi-permeable film-forming material selected from pyroxylin, polypropylene, vinyl chloride-vinylidene chloride copolymer, ethylene glycol polymethacrylate and collagen. In an embodiment, beads are formed from pitch softening at 205° C. which was melt-dispersed into water using benzene and aqueous polyvinyl alcohol as suspending agent to form beads which were heated in a fluidized bed to remove benzene, carbonised in nitrogen at 1000° C. and coated with pyroxylin. The resulting beads were said to be able to remove kidney toxin from blood and to exhibit only slight platelet adhesion, which could be avoided completely by coating with albumen.
U.S. Pat. No. 4,358,376 Moriuchi discloses a detoxifying column comprising non-coated particles of petroleum pitch which has been ultrasonically cleaned to remove dust.
U.S. Pat. No. 5,194,157 Ghezzi prefers to use vegetable-derived activated carbon in the form of microgranules which have “a multitude of minute channels opening in corresponding pores on its surface”, a contact surface area of up to 1000 m2/g and adsorption spectrum of 100-20000 D, but to use that material only in relation to an ultrafiltrate from which blood corpuscles have been removed.
RU-C-2119351 Petrik discloses separation of plasma from blood and treatment of the plasma with expanded graphite and carbon nanotubes to remove uric acid and creatine.
US-A-2004/0141932 Umekawa et al. discloses a medical adsorbent comprising activated carbon obtained by carbonising and activating a spherical phenolic resin. However, only microporoisty is indentified and there is no disclosure or suggestion of incorporating mesoporosity into the resin. GB-A-2025385 Murakama et al. discloses a spherical active carbon made by suspension polymerization of styrene/divinylbenzene, treatment of the resulting polymer with SO3 to make it infusible, followed by carbonisation and activation. Again there is no disclosure or suggestion to incorporate mesopores or active macropores, and the pores are stated to be substantially all of size<500 Å, preferably <200 Å so as to substantially avoid adsorption of high molecular weight materials such as blood serum protein.
Removing Inappropriate Amounts of Anti-Inflammatory Mediators
WO 2005/099789 Tennison, the disclosure of which is incorporated herein by reference, is concerned with the treatment of sepsis by removal of inappropriate amounts of pro or anti-inflammatory mediators e.g. IL-4, IL, 6, IL, 8, IL-10, IL-11, IL-13 and IL-1. It discloses passing blood through a monolithic porous carbon structure. Plasma components are allowed to pass through the walls of the monolith. Two streams are thereby formed: a plasma permeate stream that has passed through the walls of the monolith and a retentate stream containing the majority of the blood cells. Contrary substances are adsorbed in the walls of the monolith from the plasma permeate stream, after which the plasma permeate stream and the retentate stream are recombined. The monolithic porous carbon through which the blood plasma passes may have a mean pore size>500 nm and pores of size 2-500 nm within the carbon matrix for adsorption of middle and high molecular weight molecules. One embodiment of the monolith is tubular and another embodiment has rectangular channels of size 100-2000 μm, wall thickness 100-2000 μm and open area 30-60%. The monolithic porous structure may have a surface area of at least 600 m2/g. It may be made by partially curing a phenolic resin to a solid, in embodiments of particle size 10-100 μm, comminuting the partially cured resin, extruding the comminuted resin to give a form-stable sintered product and carbonising and activating that product. Preferred products are derived from resin of powder size 20-75 μm which provides for a macropore size of 4-15 μm and a macropore volume of about 40%.
WO 2007/070455 Gogotsi explains that even advanced activated carbons exhibit only partial performance in adsorption of large inflammatory proteins, mostly due to a limited surface area accessible to the adsorbate. It discloses a carbon composition produced from a carbon-containing inorganic precursor e.g. a ternary carbide such as Ti2AlC or carbonitride which was said to have a large surface area accessible to cytokines e.g. TNF and IL-6.
Much of the complexity of the existing systems for removing inappropriate amounts of anti-inflammatory mediators or otherwise treating blood arises from the requirement to separate the blood cells from the plasma prior to treating the plasma due to the interaction of the adsorbents with the blood. There is a requirement therefore for an efficient and cost effective extracorporeal device which allows a stream of whole blood to be treated with an effective adsorbent system for the removal of the inflammatory molecules. For such a device to be effective it is also essential that the materials used do not cause a further immune response, excessive platelet activation (blood coagulation) on the adsorbent or haemolysis of the red blood cells.